CN108271369A - It is used to prepare the new process of tryptamines and its derivative - Google Patents
It is used to prepare the new process of tryptamines and its derivative Download PDFInfo
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- CN108271369A CN108271369A CN201680061481.4A CN201680061481A CN108271369A CN 108271369 A CN108271369 A CN 108271369A CN 201680061481 A CN201680061481 A CN 201680061481A CN 108271369 A CN108271369 A CN 108271369A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
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- Thiazole And Isothizaole Compounds (AREA)
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Abstract
The present invention relates to be used to prepare the derivative of tryptamines, its substitution and be used to prepare the new process of their intermediate.
Description
Technical field
The present invention relates to the new processes for being used to prepare tryptamines and its substituted derivative.Such compound is more multiple as synthesizing
Intermediate in miscellaneous organic compound is particularly useful.
Background technology
Tryptamines and their derivative are well known multi-functional synthetic intermediates in the prior art.
According to following scheme, the conventional method for synthesizing such compound is disclosed in WO2002078693.This
Synthetic method is using corresponding indoles as starting material；Therefore the availability about starting material, there are a degree of
With the relevant limitation of those processes.
Patent application WO2011076212A2, which is disclosed, is oriented to 6- fluorine tryptamines --- for synthesizing Lu-AE-58054
The critical segment of (Idalopirdine, the compound of formula I in the application) --- synthetic route, the 6- fluorine tryptamines is that have
Effect and selectivity 5-HT6Receptor antagonist.Entire synthetic schemes is shown below.The major defect of this synthesis is clearly to make
With the cyanide salt for being used to form intermediate cyanogen methyl -6- fluoro indoles.Make in addition, this synthetic method also needs to supply 6- fluoro indoles
For key starting material.
The demand of the technique of tryptamine derivatives is prepared accordingly, there exist improvement, since simpler and available material
And chemical reagent safe to use.
Invention content
The object of the present invention is to provide for from the technique of Formula II preparation of compounds of formula Compound I or its salt.
The further object of the present invention is to provide the technique for being used to prepare compound of formula I as described above or its salt, described
Technique further comprises formula III compound being converted into Formula II compound.
It is a further object to provide for from the technique of Formula II a preparation of compounds of formula Ia compounds.
Another purpose again of the present invention is to prepare organic compound using Formula II compound.
Definition
Term " alkyl " means formula CmH2m+1Monovalent straight chain or branched group or formula CmH2m-1Cyclic group, wherein m is
The number of carbon atom.Preferred alkyl group is C1-20Alkyl group, more preferably C1-10Alkyl group, more preferably C1-8Alkyl
Group.Particularly preferred alkyl group includes, for example, methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl
Base, n-pentyl, n-hexyl, n-heptyl, n-octyl.
Term " halogenated alkyl " refer in one or more positions of alkyl chain substitution there are one or multiple halogen atoms
Alkyl group.
Term " alkenyl " means monovalent straight chain or branch containing one or more carbon-to-carbon double bonds and at least two carbon atom
Part.These parts meeting formula CmH(2m-1), wherein m is the number of existing carbon atom.Preferred alkenyl group is C2-20Alkenyl
Group, still more preferably C2-10Alkenyl group, still more preferably C2-10, still more preferably C2-8Alkenyl group.
Term " alkynyl " means monovalent straight chain or branch containing one or more carbon-carbon triple bonds and at least two carbon atom
Part.These parts meeting formula CmH(2m-3), wherein m is the number of existing carbon atom.Preferred alkynyl group is C2-20Alkynyl
Group, still more preferably C2-10Alkynyl group, still more preferably C2-10Alkynyl, still more preferably C2-8Alkynyl group.
The C6-18 cyclic aromatic radicals that term " aryl " reference is formed by one or more rings, can optionally replace
There are one or multiple substituent groups.Preferably, aromatic ring is C6-10 member ring systems.Typical example includes phenyl, naphthalene and anthryl.
Term " heteroaryl " refers to cyclic aromatic radical as defined above, wherein one or more carbon atoms by one or
Multiple hetero atoms selected from nitrogen, sulphur or oxygen substitute, and the hetero atom can be optionally substituted with one or more substituent groups.It is preferred that
Ground, aromatic heterocycle are pyrazoles, pyrroles, imidazoles, furans, thiophene, benzo [b] thiophene, pyrazine, pyridine, pyrimidine, pyridazine.
Term " substituent group " refers to：
Alkyl is optionally substituted with alkoxy or hydroxyl；
Cycloalkyl；
Aryl, be optionally substituted with hydroxyl, alkyl, alkoxy, halogen, benzyloxy, carboxyl, alkoxy carbonyl group, acylamino-,
N- alkyl amidos, sulfonamido (sulfonylamido), cyano, halogenated alkyl, halogenated alkoxy, nitro；
Heteroaryl；
Heterocycle；
Alkenyl；
Alkynyl；
Halogen atom；
Hydroxyl group；
Alkoxy or aryloxy group；
Alkoxy or aryloxycarbonyl group；
Mercapto groups；
Sulfide group；
Thioester group；
Aldehyde group；
Aryl or alkylcarbonyl-residues；
Carboxylic group；
The carboxylic group being esterified with alkyl or aryl group；
Amide group；
Amine groups；
Nitrile group；
Alkyl or aryl sulfonyl；
Acylamino- sulfonyl (amidosulphonyl)；
Preferably substituent group is
Alkyl is optionally substituted with alkoxy, hydroxyl；
Cycloalkyl；
Aryl；
Heteroaryl；
Alkylaryl or miscellaneous alkyl aryl；
Halogen atom；
Hydroxyl group；
Alkoxy or aryloxy group；
Alkoxy or aryloxycarbonyl group；
Aryl or alkylcarbonyl-residues；
Carboxylic group；
The carboxylic group being esterified with alkyl or aryl group；
Amide group；
Amine groups；
Term " reducing agent " means the reagent that can cause reduction in compound.In the case of organic compound, also
The state of oxidation that original can be defined as wherein carbon atom is reduced, or in other words, lead to the reaction of carbon atom clear electronics.
During reduction reaction, more than one carbon atom or functional group can be restored.It can use in one step more than one
Reducing agent.
The acceptable salt of this paper prepare compounds includes its suitable acid-addition salts.The summary of suitable pharmaceutical salts can be with
It is found in Berge et al., J.Pharm.Sci., 66,1,19 (1977).Salt is by for example, what following acid was formed：Strong acid
Such as inorganic acid, such as sulfuric acid, phosphoric acid or halogen acids；Strong organic carboxyl acid, such as unsubstituted or substituted (for example, being optionally substituted by halogen) 1
To the alkane carboxylic acid of 4 carbon atoms, such as acetic acid and trifluoroacetic acid；Saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, amber
Platinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid (TPA) (tetraphthalic)；Hydroxycarboxylic acid, such as ascorbic acid,
Glycolic (glycolic), lactic acid, malic acid, tartaric acid or citric acid；Amino acid, such as aspartic acid or glutamic acid；Benzene first
Acid；Or organic sulfonic acid, such as substituted or unsubstituted (for example, being optionally substituted by halogen) (C1-4)-alkyl-or aryl-sulfonic acid such as
Methane-or p-methyl benzenesulfonic acid.
The term " one (a) " that uses in the context describing the invention and " a kind of (an) " and " should (it is described,
The) " and similar indicant should be interpreted to cover both odd number and plural number, unless otherwise indicated herein or with upper and lower civilization
Aobvious contradiction.For example, unless otherwise indicated, phrase " compound " is understood to refer to the various compounds of the present invention or especially retouch
The aspect stated.Unless otherwise indicated, provided herein is all exact values represent corresponding approximation (for example, about special factor
Or all accurate example values of measurement offer can consider and also provide corresponding approximate measurement, in appropriate circumstances
It is modified by " about ").The present invention is used about the term such as "comprising" of one or more elements, " having ", " comprising " or " is contained
By " any aspect or aspect be described herein it is intended that " being made of the specific one or more elements ", " substantially by the tool
Body one or more elements form " or " generally including " the specific one or more elements the present invention similar aspect or
Aspect provides support, unless otherwise prescribed or is apparently contradicted in the context (for example, being described herein as including the combination of key element
Object is interpreted as also illustrating the composition being made of the element, unless otherwise prescribed or is apparently contradicted in the context).
Specific embodiment
The present invention is provided to preparation of compounds of formula I or the modified techniques of its salt.It is simpler that the technique of the present invention provides use
The advantages of starting material (benzene derivative replaced) of list.Compound of formula I is in four step Nei Ke get from starting material
It arrives.Using simple and safety (most important) reagent, specifically avoiding using has the shortcomings that self-evident cyanogen for reaction
Compound compound.
It is therefore an object of the present invention to provide the technique for being used to prepare compound of formula I or its salt, wherein phenyl ring can be by one
A or multiple substituent group substitutions,
The technique includes and Formula II compound is converted into compound of formula I or its salt, wherein benzene in the presence of a reducing agent
Ring can be substituted by one or more substituents.
Formula II compound is converted into compound of formula I to include restoring more than one functional group.By destroying and oxygen atom
Double bond simultaneously generates and restores carbon -1 with the double bond of another carbon atom.By destroying and the singly-bound of oxygen atom and generation and another
The double bond reduction carbon -2 of carbon atom.Nitrile group is reduced to corresponding benzylidene amino group.
Since multiple functional groups need to be reduced to generate compound of formula I, various reducing agents can be used.It can be with
It is desirable that, two or more reagents are combined with in-situ preparation reducing agent or the property for combining them.Furthermore it is possible to it selects
Various reaction conditions, such as reaction time, solvent, temperature, equivalent, equipment, initial purity and raw material and whether there is air.Technology people
All that factor known to member allows control to restore, this can result in the centre of the various states of oxidation as outlined above
Body forms compound of formula I.Those intermediates are included by the technique of the present invention and form a part for its range.Among those
The separation of body is optional.
Formula IV and Formula VII compound are intermediates as described above and will be discussed in further detail.
If for dry type reduction reaction reducing agent disclosed in textbook well known in the art, such as March's
Advanced Organic Chemistry, M.B.Smith ＆ J.March, John Wiley ＆ Sons, ISBN 13:978-
0-471-72091-1.Newer discovery in compound reduction field is related to the Lewis Acids and Bases that are obstructed described in scientific literature
(FLP, frustrated Lewis pair) is restored.Representative example is：a)Curr.Chem.2013,332,
D.W.Stephan,G.Erker；b)Org.Proc.Res,Dev.2014,18,385,L.J.Hounjet,D.W.Stephan；c)
J.Am.Chem.Soc.2015,137,10018, D.W.Stephan and references cited therein.Representative FLP reagents are
p-(Mes2P)C6F4[B(C6F5)2]、B(C6F5)3、Mes2PC2H4B(C6F5)3、C10H6(PPh2)2/B(C6F5)3。
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron (boran halides), boron hydride,
Metal hydride, metallic catalyst, metal cation, metallic amalgam, hydrazine, silane, siloxanes, even bisulfites, two sulfurous
Hydrochlorate, sulfonate, phosphine compound, phosphite, hypophosphites (hypophosphites), phosphorous acid, carbon, carbon monoxide, oxalic acid,
Formic acid, ascorbic acid, FLP reagents, hydrogen and its mixture.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, gold
Metal catalyst, FLP reagents, hydrogen and its mixture.
Formula II compound is converted into compound of formula I to carry out in organic solvent or its mixture.It is preferred organic
Solvent is aprotic polar organio solvent.
The temperature of reaction can be from 0 DEG C to the boiling point of solvent.Preferred temperature is from 0 DEG C to 160 DEG C.
The further object of the present invention is to provide the midbody compound of process above.
The further object of the present invention is to provide the technique for being used to prepare Formula IV compound, and the technique is included in reducing agent
In the presence of Formula II compound is converted into Formula IV compound.About three above-mentioned functional groups, the reducing agent should be able to
Partial reduction Formula II compound.Correspondingly, nitrile carbon is reduced to respective amine, carbon -2 by eliminate hydroxyl group reduction and
Carbon -1 is partly alcohol from carbonyl reduction.
As above it has disclosed, more than one reducing agent can be used for causing this conversion.In addition, reaction condition disclosed above
Effect control this reduction in an identical manner.
Preferred reducing agent is borine, boron hydride, metal hydride and its mixture.
It is a further object to provide the technique for being used to prepare Formula VII compound, the technique is included in reduction
Formula II compound is converted into Formula VII compound in the presence of agent.The reducing agent should be able to only restore formula as described above
Two in three functional groups of II compounds.Correspondingly, by destroying with the double bond of oxygen atom and generating double bond with carbon -2
Carbon -1 is restored, the carbon -2 restored simultaneously by eliminating hydroxyl group.Nitrile part keeps complete.
As above it has disclosed, more than one reducing agent can be used for causing this conversion.In addition, reaction item disclosed above
The effect of part controls this reduction in an identical manner.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, metal
Catalyst, metal sun from, metallic amalgam, hydrazine, silane, siloxanes, bisulfites, dithionite, sulfonate, phosphine
Object, phosphite, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, hydrogen and it is mixed
Close object.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, gold
Metal catalyst, FLP reagents, hydrogen and its mixture.
Another object of the present invention is with prepare compound I, VI and VII using Formula II compound.In preferred implementation side
In formula, it in the fluorine atom and Formulas I, VI and VIl compounds of two ring core 6 is respectively Formulas I a, VIa and VIIa that substituent A, which is,
Compound.
In a preferred embodiment of the invention, the technique for being used to prepare Formulas I a compound or its salts, the work are provided
Skill includes Formula II a compounds are converted into Formulas I a compounds in the presence of a reducing agent.Reducing agent for this conversion should be able to
Enough restore all functional groups being stated as above, i.e. carbon -1, carbon -2 and nitrile group.This may need more than one reducing agent and as above
The various conditions discussed.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, metal
Catalyst, metal cation, metallic amalgam, hydrazine, silane, siloxanes, bisulfites, dithionite, sulfonate, phosphine
Object, phosphite, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, hydrogen and it is mixed
Close object.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, gold
Metal catalyst, FLP reagents, hydrogen and its mixture.
Formula II a compounds are converted into Formulas I a compounds to carry out in organic solvent or its mixture.Preferably have
Solvent is aprotic polar organio solvent.
The temperature of reaction can be from 0 DEG C to the boiling point of solvent.Preferred temperature is from 0 DEG C to 160 DEG C.
Formula II a compounds are converted into Formulas I a compounds can be related to a variety of intermediates as described above.
The further object of the present invention is to provide the midbody compound and its preparation process.
The further object of the present invention is to provide the technique for being used to prepare Formula IV a compounds, and the technique is included in as above
Formula II a compounds are converted into Formula IV a compounds in the presence of the reducing agent.
Preferred reducing agent is borine, boron hydride, metal hydride and its mixture.Preferred reducing agent is gold
Belong to hydride.Even more preferably reducing agent is bis- (2- methoxy ethoxies) sodium aluminum hydrides.
It is a further object to provide the technique for being used to prepare Formula VII a compounds, the technique is included in as above
Formula II a compounds are converted into Formula VII a compounds in the presence of the reducing agent.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, metal
Catalyst, metal cation, metallic amalgam, hydrazine, silane, siloxanes, bisulfites, dithionite, sulfonate, phosphine
Object, phosphite, hypophosphites, phosphorous acid, carbon, carbon monoxide, oxalic acid, formic acid, ascorbic acid, FLP reagents, hydrogen and it is mixed
Close object.
Preferred reducing agent is borine, the mixture of boron hydride and halogenation boron, boron hydride, metal hydride, gold
Metal catalyst, FLP reagents, hydrogen and its mixture.
In a preferred embodiment of the invention, the technique for being used to prepare Formulas I a compound or its salts, the technique are provided
Including Formula II a compounds are converted into Formulas I a compounds in the presence of a reducing agent, it is characterised in that first by Formula II a compounds
Formula VII a compounds are converted into, and Formula VII a compounds are then converted into Formulas I a compounds.The intermediate compound of Formula VII a
Object can be optionally separated.
In a preferred embodiment of the invention, above-mentioned technique is carried out in the case where not detaching Formula VII a compounds.
The further object of the present invention is to provide the technique for being used to prepare compound of formula I as defined above or its salt, described
Technique further comprises reacting for formula III compound and cyanoacetic acid (VIII), to provide Formula II compound as defined above,
Middle phenyl ring can be substituted by one or more substituents.
Formula III compound can be carried out with reacting for cyanoacetic acid in organic solvent or its mixture.It is preferred organic
Solvent is polar organic solvent.Preferred organic solvent is aprotic polar organio solvent.
The temperature of reaction can be from 20 DEG C to the boiling point of solvent.Preferred temperature is from 20 DEG C to 160 DEG C.
In a preferred embodiment of the invention, compound of formula I is Formulas I a compounds, and Formula II compound is Formula II a chemical combination
Object and formula III compound are formula III a compounds.
The further object of the present invention is to provide for from the work of Formula II preparation of compounds of formula VI compounds as described above
Skill, the technique further comprise reacting for formula III compound as defined above and cyanoacetic acid (VIII), to provide as above institute
The Formula II compound stated.
In a preferred embodiment of the invention, formula III compound is formula III a compounds, and Formula II compound is Formula II a
Compound and Formula IV compound are Formula IV a compounds.
The further object of the present invention is to provide for from the work of Formula II preparation of compounds of formula VII compounds as described above
Skill, the technique further comprise reacting for formula III compound as defined above and cyanoacetic acid (VIII), to provide as above institute
The Formula II compound stated.
In a preferred embodiment of the invention, formula III compound is formula III a compounds, and Formula II compound is Formula II a
Compound and Formula VII compound are Formula VII a compounds.
It is described it is a further object to provide the technique for being used to prepare Formulas I a compound or its salts as defined above
Technique further comprises by the way that formula IV a compounds are converted into Formula V a compounds with chloraldurate and azanol reaction and are passed through
Formula V a is converted into formula III a compounds by the cyclisation of formula Va compounds in presence of an acid.
Formula IV a compounds are converted into Formula V a compounds to carry out in polar solvent or water.
Formula V a compounds are converted into formula III a compounds to be related toUnder the acid condition of acid
It carries out.Non-limiting examples are halogen acids, sulfuric acid, acetic acid or similar sour.The step can also in the case of lewis acid into
Row.PreferablyAcid.
Another purpose again of the present invention is to provide Formula II compound.
In a preferred embodiment of the invention, Formula II compound is Formula II a compounds.
According to the prior art, compound of formula I (tryptamines) as defined above and its salt can be used for preparing organic compound.It is preferred that
Organic compound be pharmaceutical organic compound.Preferred organic compound is the compound containing indoles.
Compound containing indoles and its property in N.K.Kaushik, N, Kaushik, P.Attri, N, Kumar,
C.H.Kim, A.K.Verma and E, summary " biomedical importance (the Biomedical importance of indoles of H.Choi
Of indoles) ", Molecules is discussed in 2013,18,6620.
Application of the compound of formula I (tryptamines) in the compound containing indoles is prepared includes preparing polycyclic compound, this is more
Cycle compound includes two ring cores of indoles condensed with another ring, and the polycyclic compound can be monocyclic or polycyclic.
Example from this field can be found following：
" pass through the naked amino of direct amino Cyclization-pyrrolo- indoline (Synthesis of naked of tryptamines
amino-pyrroloindoline via direct aminocyclization of trytamine)”,
Org.Biom.Chem.2015,13,5381,Z.Shen,Z.Xia,H,Zhao,J.Hu,X.Wan,Y.Lai,C,Zhu,W,Xie；
" pyrrolo- indoline and furans and two are synthesized with the cascade dearomatization of carbonium ion by indole derivatives
Hydrogen indoles (Synthesis of pyrroloindolines and furoindolines via cascade
dearomatization of indole derivatives with carbenium ion)”,Chem.Comm.2015,51,
5971,C,Liu,Q.Yin,L.-X.Dai,S.-L.You；
" by the cascade asymmetric dearomatization of Michael/Friedcl-Crafts types to build polycyclic spiral shell dihydro Yin
Diindyl (Asymmetric Dearomatization of Indoles through a Michael/Friedcl-Crafts-
Type Cascade To Construct Polycyclic Spiroindolines)”Angew.Chem.Int.Ed.2015,
54,4032,X.Zhao,X.Liu,H.Mei,J.Guo,L.Lin,X.Feng；
" facilitate preparation using galvanochemistry as the Nazlinine of enabling tool and the small library of indole alkaloid
(Expedient Preparation of Nazlinine and a Small Library of Indole Alkaloids
Using Flow Electrochemistry as an Enabling Technology)”,Organic Letters 2014,
16(17),4618,M.A.Kabeshov,B.Musio,P.R.D.Murray,D.L.Browne,S.V.Ley；
" indoles of nitrogen connection of rhodium (I) catalysis and the cycloisomerisation of alkylidene cyclopropane：Easily obtain polycyclic indoles
Derivative (Rhodium (I)-Catalyzed Cycloisomerization of Nitrogen-Tethered Indoles
and Alkylidenecyclopropanes:Convenient Access to Polycyclic Indole
Derivatives)”Chem.Eur.12013,19,13668,D.-H.Zhang,X.-Y.Tang,Y,Wei,M.Shi；
" Cascading Methods of golden (I) catalysis are for tryptamines Quito Huan Te of the synthesis as α 1- adrenoceptor antagonists
Different in nature stent (Gold (I)-Catalyzed Cascade Approach for the Synthesis of Tryptamine-
Based Polycyclic Privileged Scaffolds asα1-Adrenergic Receptor Antagonists)”,
Journal of Organic Chemistry,2013,78,10802,Z.Li,J.Li,N.Yang,Y.Chen,Y,Zhou,
X.Ji,L.Zhang,J.Wang,X.Xie,H.Liu；
" the enantioselectivity hydrogen amination of gold and the catalysis of BINOL- phosphorus/N- sulphonyl imines ion cyclisation cascade (Gold
and BINOL-Phosphoric Catalyzed Enantioselective Hydroamination/N-
Sulfonyliminium Cyclization Cascade) " Organic Letters, 2013,15,4330,
A.W.Gregory,P.Jakubec,P.Turner,D.J.Dixon；
" the enantioselectivity Michael additions of urea derived from color ammonia/imines ion cyclisation cascade
(Enantioselective Michael Addition/Iminium Ion Cyclization Cascades of
Tryptamine-Derived Ureas)”Organic Letters,2013,15,2946,I.Aillaud,D.M.Barber,
A.L.Thompson,D.J.Dixon；
" cascade process started by gold catalysis obtains the hexahydro quinolizine ketone (Access that the aromatic hydrocarbons rich in electronics condenses
to Electron-Rich Arene-Fused Hexahydroquinolizinones through a Gold-
Catalysis-Initiated Cascade Process)”Angewandte Chemie International Edition
2012,51(29),7301,L.Liu,L.Zhang；
" it is condensed racemization and diastereomeric choosing in the Pictet-Spengler of microwave radiation technology solvent-free and without catalyst
Selecting property structure indole alkaloid (Racemic and diastereoselective construction of indole
alkaloids under solvent-and catalyst-free microwave-assisted Pictet-Spengler
condensation)”Green Chemistry 2012,14,909,M.Jida,O.-M.Soueidan,B.Deprez,
G.Laconde,R.Deprez-Poulain；
" enantioselectivityAcid catalyzed N- acyl imines cyclisation cascade (Enantioselective Acid-Catalyzed N-Acyliminium Cyclization Cascades)”J.Am.Chem,
Soc.2009,131,10796,M.E.Muratore,C.A.Hollo way,A,W.Pilling,R.I.Storer,G,
Trevitt,D,J.Dixon；
" the enantioselectivity Pictet-Spengler type rings of hydroxyl lactam：It is supplied by the hydrogen bond that cation combines
Body is catalyzed (Enantioselective Pictet-Spengler-Type Cyclizations of Hydroxy-lactams:
H-Bond Donor Catalysis by Anion Binding)”J.Am.Chem.Soc.2007,129,13404,
I.T.Raheem,P.S.Thiara,E.A.Peterson,E.N.Jacobsen；
" Spirocyclic cyclohexane derivatives (Spirocyclic cyclohexane derivatives) ",
WO2004043967；
" Azepinoindole derivatives (the Azepinoindole derivatives as medicament
pharmaceutical agents)”,WO2005056554；
" phenyl acetamide derivative and its heterocyclic analogs (Phenethylamide derivatives and their
heterocyclic analogues)”,WO2010044054；
" antitumoral analogue (Antitumoral analogs) ", WO2003014127；
" there is substituted B-carboline (the Substituted beta-carbolines with of ikb kinase inhibiting activities
ikb-kinase inhibiting activity)”,WO2001068648；
" to treat the B-carboline of inflammatory disease (Beta-carbolines useful for treating
Inflammatory disease) ", WO2004092167, WO2005111037,
Further application of the compound of formula I (tryptamines) in the compound containing indoles is prepared is made in itself including the use of tryptamines
Small modification is carried out for structural unit or to its core.
For example, according to WO2002078693, using Formulas I a compounds to synthesize Lu-AE-58054 --- its to be effective and
The 5-HT of selectivity6Receptor antagonist.Further example from the prior art is：
" design of the GluN2C- selectivity synergist of new range a kind of, synthesis and structure-activity relationship (Design,
Synthesis,and Structure-Activity Relationship of a Novel Series of GluN2C-
Selective Potentiators)”,J.Med.Chem.2014,57,2334,S.S.Zimmerman,A.hatri,
E.C.Gamier-Amblard,P.Mullasseril,N,L,Kurtkaya,S.Gyoneva,K.B.Hansen,
S.F.Traynelis,D.C.Liotta；
" new melatonin-N, N- dibenzyl (N- methyl) amine heterozygote：With anti-oxidant, cholinergic and neuroprotection
Effective neurogenic agent of property --- drug (New Melatonin-N, N- as the innovation for Alzheimer disease
Dibenzyl(N-methyl)amine Hybrids:Potent Neurogenic Agents with Antioxidant,
Cholinergic,and Neuroprotective Properties as Innovative Drags for Alzheimer'
s Disease)”J.Med.Chem.2014,57,3773,B.Lopez-Iglesias,C.Perez,J.A.Morales-
Garcia,S.Alonso-Gil,A.Perez-Castillo,A.Romero,M.G.Lopez,M,Villarroya,S.Conde,
M,I.Rodriguez-Franco；
" for treating the indole amides derivative of neurodegenerative disease and related compound (Indole amide
derivatives and related compounds for use in the treatment of
neurodegenerative diseases)”,WO2010142081；
" as 5-HT6Tryptamines sulfonamide (the Trytamine sulfonamides as 5- of antagonist
HT6antagonists)”,WO2009073118；
" pyrimidine derivatives (the Pyrimidine derivatives as ALK- as ALK-5 inhibitor
5inhibitors) ", WO2008006583；
" compound and its application (Piperidine-containing compounds and use containing piperidines
thereof)”,WO2010080864；
" pyrazinone thrombin inhibitors (Pyrazinone thrombin inhibitors) ", WO9740024；
" new substituted tryptamines, phenylalkylamine and related compound (Novel substituted tryptamines,
phenalkylamines and related compounds)”,WO9526723。
Therefore, it is a further object of the invention that using Formulas I as defined above and Formula II compound (according to the present invention into
It is prepared by row) to prepare organic compound.
Another purpose again of the present invention is, in being synthesized by the use of Formula II compound as defined above as organic compound
Intermediate.Its serviceability obtains the property of compound of formula I or its salt derived from providing.Formula II compound is preferably Formula II a compounds.
Organic compound can be preferably pharmaceutical organic compound.Even further preferably, organic compound can be the change containing indoles
Close object.It is more preferred still that the compound containing indoles is Idalopirdine.
The further object of the present invention is to be used to prepare the technique of organic compound, and the technique is included in depositing for reducing agent
The step of Formula II compound is converted into compound of formula I lower, and compound of formula I is further converted into organic compound.Formula
II compounds are preferably Formula II a compounds.Organic compound can be preferably pharmaceutical organic compound.Even further preferably, have
Machine compound can be the compound containing indoles.It is more preferred still that the compound containing indoles is Idalopirdine.
Embodiment
Unless otherwise noted, it can be obtained or by this field skill from easy commercially available source for the material of embodiment
Standard method known to art personnel synthesizes.
Embodiment 1：The preparation of Formula V a compounds
In RB bottles, at 25-30 DEG C, by the softening of 6.0 grams of (0.054 mole) loading 375ml of 3- fluoroanilines (IVa)
Water (D.M.water).10.74 grams of chloraldurates (0.065 mole), 13.68 grams of hydroxylamine hydrochlorides (0.197 are added to above-mentioned solution
Mole) and 61.38 grams of sodium sulphate (0.432 mole).Reaction mass is warmed to 50 DEG C and 5 hours of stir about.Make reactant
Expect Slow cooling (25-30 DEG C).Continue to be stirred overnight at ambient temperature.At 25-30 DEG C, under stiring, mixed to reaction
Object addition 18.6ml hydrogen chloride (2N), and stir about 30 minutes.By Buchner funnel filter out the solid of precipitation and with 24ml it is cold
Softened water hydro-peening filter cake.It removes wet cake and is rotarily dried 60 minutes under 38-40 DEG C of vacuum, to provide 8.628 grams crude
Formula V a compounds.
1H NMR(300MHz,DMSO-d6)12.2(s,1H),10.4(s,1H),7.7(m,1H),7.6(s,1H),7.5
(m,1H),7.4(dd,J1=15.1Hz, J2=8.1Hz, 1H), 6.9 (td, J1=8.4Hz, J2=2.4Hz, 1H).13C NMR
(75MHz,DMSO-d6)162.0,160.6,143.9,140.2,130.4,115.6,110.3,106.6。
Embodiment 2：The preparation of formula III a compounds
In RB bottles, 30ml sulfuric acid is loaded under stiring and is heated up to 70 DEG C.Formula V a compounds are added in aly
Crude wet cake (8.628 grams) simultaneously continues to stir at 80-90 DEG C.When the reactions are completed, reaction mass is made to be cooled to 25-30 DEG C.
In RB bottles, load 282ml softened waters and ice and 180ml ethyl acetate and be vigorously stirred.Reaction mixture is added in RB bottles.
Reaction mixture is made to be heated up to 25-30 DEG C and further stir about 10 minutes.Collected organic layer.It is (every with 180ml ethyl acetate
It is secondary) extraction water layer is twice.It is dried over sodium sulfate with reference to organic layer, it filters out and evaporates solvent until being completely dried, to provide
6.914 grams of crude formula III a compounds.
1H NMR(300MHz,DMSO-d6)11.2(br,1H)7.6(dd,J1=8.3Hz, J2=5.8Hz, 1H), 6.9
(ddd,J1=10.4Hz, J2=8.5Hz, J3=2.2Hz, 1H), 6.7 (dd, J1=9.2Hz, J2=2.2Hz, 1H).13C NMR
(75MHz,DMSO-d6)182.3,168.0,159.7,153.3,127.8,114.7,109.6,100.2。
Embodiment 3：The preparation of Formula II a compounds
In RB bottles, at 25-30 DEG C, stirring ground 3.36 grams of crude formula III a compounds (0.0203 mole) of loading are simultaneously molten
Solution is in 33.6mL tetrahydrofurans.1.902 grams of cyanoacetic acids (0.0224 mole) and 2.7mL triethylamines are added to clear solution
(0.0194 mole).Heating reaction mass is stirred overnight with flowing back and continuing.When the reactions are completed, reaction mass is made to cool down (25-
30℃).Concentrated solvent is until being completely dried.168mL softened waters are added to oiliness residue and with 336mL ethyl acetate (each)
Extraction is three times.It is dried over sodium sulfate with reference to organic layer, it filters and evaporates solvent until being completely dried, to provide 4.116 grams thick
Standard IIa compounds.
1H NMR (300MHz, DMSO-d6) 7.47 (dd, J1=8.2Hz, J2=5.6Hz, 1H), 6.89-6.82 (m,
1H), 6.7 (dd, J1=9.2Hz, J2=2.4Hz, 1H), 6.64 (s, 1H), 3.36 (s, 1H), 3.09-2.94 (m, 2H).13C
NMR(75MHz,DMSO-d6)177.4,163.6,143.9,143.8,126.2,117.4,108.5,98.7,72.0,26.4。
Embodiment 4：The preparation of Formulas I a compounds as hydrochloride
In RB bottles, 0.2 gram of Formula II a compounds (0.00097 mole) are loaded under argon atmosphere and at 25-30 DEG C
It is diluted with 5ml dry tetrahydrofurans.To clear solution addition 1.2ml borane dimethyl sulphides (in 2M, THF) (0.0024 mole)
And continue to stir under environment temperature (25-30 DEG C).When starting material consumes, added at 25-30 DEG C to reaction mass
0.085 gram of sodium borohydride (0.0023 mole).When midbody compound consumes, 10ml sodium hydroxides are added to reaction mass
(10%) it and is vigorously stirred.Collected organic layer is simultaneously concentrated to dryness.It is diluted with 5ml dichloromethane and adds 5ml hydrogen chloride (6N).
It extracts and collects water layer.Distilling off solvent is until being completely dried under reduced pressure, to provide 0.067 gram of Formulas I aization as hydrochloride
Close the light yellow solid of object.
1H NMR(300MHz,CD3OD)7.56(dd,J1=8.6Hz, J2=5.2Hz, 1H), 7.21 (s, 1H), 7.10
(dd,J1=10.0Hz, J2=2.1Hz, 1H), 6.85 (td, J1=9.7Hz, J2=2.3Hz, 1H), 3.3 (s, 2H), 3.25
(tr, J=7.2Hz, 2H), 3.15 (tr, J=7.3Hz, 2H).13C NMR(75MHz,CD3OD)159.0,136.9,123.5,
123.4,118.5,109.2,107.1,97.0,39.9,23.0。
Embodiment 5：The preparation of Formulas I a compounds as hydrochloride
In RB bottles, 0.5 gram of Formula II a compounds (0.00243 mole) are loaded under argon atmosphere and at 25-30 DEG C
It is diluted with 15ml dry tetrahydrofurans.To clear solution addition 4.2ml borane dimethyl sulphides (in 2M, THF), (0.0084 rubs
You) and continue to stir under environment temperature (25-30 DEG C).When starting material consumes, added at 25-30 DEG C to reaction mass
0.23 gram of sodium borohydride (0.0061 mole).When midbody compound consumes, cooling reaction mass (0-5 DEG C) simultaneously adds
42ml sodium hydroxides (10%) are simultaneously vigorously stirred.Collected organic layer and (0.0243 rubs using 1.2ml hydrogen chloride (2M, ether in)
You) acidification.Distilling off solvent is until being completely dried under reduced pressure.20ml dichloromethane is added to residue.Pass through Buchner funnel
Filtering.Yellowing (off-yellow) solid of the Formulas I a compounds as hydrochloride of 0.5 gram of separation.
Embodiment 6：The preparation of Formulas I a compounds
In RB bottles, 20ml 1,2- dimethoxy-ethanes are loaded, and then add 0.64 gram of sodium borohydride (0.0169
Mole).Suspended material is cooled down to (0-5 DEG C) and the Formula II a compounds of 1.0 grams of addition and 4.4ml boron trifluoride ether (0.0347
Mole).Reaction mass is made to be heated up to room temperature and continues stirring until reaction is completed.Cooling reaction mixture (0-5 DEG C) is used in combination
50ml methanol is quenched.Make heating and concentrated solvent is until being completely dried.50ml ethyl acetate is added to suspended material and 25ml satisfies
And sodium bicarbonate.Water layer is extracted again with 50ml ethyl acetate.It is dried over sodium sulfate and concentrate until drying with reference to organic layer,
The crude Formulas I a compounds as free alkali to provide 1.3 grams.
Embodiment 7：The preparation of Formula IV a compounds
In RB bottles, load 0.1 gram of compound IIa (0.485 mM) and dilute (25-30 with 2ml tetrahydrofurans
℃).Bis- (2- methoxy ethoxies) sodium aluminum hydrides (red aluminum) (0.00145 mole) of 0.42ml are added to clear solution.Work as reaction
During completion, 5ml softened waters and 10ml ethyl acetate are added to reaction mixture.Collected organic layer.It is extracted with 10ml ethyl acetate
Water layer.It is extracted with reference to organic layer and with 5ml softened waters.Collected organic layer, it is dried over sodium sulfate, it filters and concentrates until drying,
To provide 0.124 gram of crude red oil.Above-mentioned grease is purified using column chromatography to detach 0.054 gram of light yellow oil
Shape object (Formula IV a compounds).
1H NMR(300MHz,DMSO-d6)7.03(dd,J1=7.9Hz, J2=6.2Hz, 1H), 6.24 (m, 1H), 6.13
(m,1H),4.7(s,1H),2.88(m,1H),2.52(m,1H),1.94(m,3H)。
Embodiment 8：The preparation of Formula VII a compounds
In RB bottles, at 25-30 DEG C, stirring ground loads 0.1 gram of crude Formula II a compounds (0.485 mM) simultaneously
It is dissolved in 2ml tetrahydrofurans.To clear solution addition 0.55ml borane dimethyl sulphides (in 2M, THF) (0.0023 mole).
When the reactions are completed, 5ml ethyl acetate and 5ml hydrogen chloride (1N) are added and is stirred.Collected organic layer, dried over sodium sulfate, mistake
It filters and evaporates solvent until being completely dried, to provide 0.1 gram of crude Formula VII a compounds.Purified with column chromatography, provide 0.74
Gram the compound.
1H NMR(300MHz,CDC13)8.17(br,1H),7.50(dd,J1=8.6Hz, J2=5.2Hz, 1H), 7.21
(s, 1H), 7.08 (d, J=9.5Hz, 1H), 6.96 (tr, J=9.2Hz, 1H), 3.82 (s, 2H).
Embodiment 9：The preparation of Formula VII a compounds
In RB bottles, under argon atmosphere, at 25-30 DEG C, 0.1 gram of Formula II a compounds (0.485 mM) are loaded
And it is dissolved in 2ml dry tetrahydrofurans.0.055 gram of sodium borohydride (1.455 mMs) is added to clear solution and continues to stir
It mixes.0.3ml boron trifluoride ether (1.11 mMs) is added dropwise to reaction mass and continues to stir at ambient temperature.Thin-layer chromatography
Analysis shows that the consumption of starting material and the formation of Formula VII a compounds.
Embodiment 10：The preparation of Formula VII a compounds
In RB bottles, under argon atmosphere, at 25-30 DEG C, load 1.4 grams of crude Formula II a compounds and be dissolved in
In 20ml dry tetrahydrofurans.6.1ml borane dimethyl sulphides (in 2M, THF) (12.12 mMs) are added dropwise simultaneously to clear solution
Continue to stir at ambient temperature.0.46 gram of sodium borohydride (12.12 mMs) is added to reaction mass and continues to stir.It is thin
Analysis is analysis shows that the consumption of starting material and the formation of Formula VII a compounds layer by layer.
Claims (15)
1. be used to prepare compound of formula I or the technique of its salt, wherein aromatic ring optionally replace there are one or it is multiple be selected from
Under substituent group：Alkyl, substitution have the aryl, alkyl, alkane that the alkyl of alkoxy or hydroxyl, cycloalkyl, aryl, substitution have hydroxyl
Oxygroup, halogen, carboxyl, alkoxy carbonyl group, acylamino-, N- alkyl amidos, sulfonamido, cyano, halogenated alkyl, haloalkoxy
Base, nitro, heteroaryl, heterocycle, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, aryloxy group, alkoxy carbonyl group, aryloxycarbonyl,
Sulfydryl, alkyl thioether, aryl thioethers, alkylthio acid esters, aryl thioesters, aldehyde group, aryl carbonyl, alkyl-carbonyl, carboxylic
Base, carboxyl, amide, amine, nitrile, alkyl sulphonyl, aryl sulfonyl and the acylamino- sulfonyl being esterified with alkyl or aryl, it is described
Technique includes Formula II compound is converted into compound of formula I in the presence of a reducing agent, and wherein aromatic ring optionally replaces and has
One or more substituent group as defined above.
2. the technique according to claim 1 for being used to prepare compound of formula I or its salt, further comprises formula III chemical combination
The step of object is reacted with cyanoacetic acid VIII with shape compound of formula II, wherein aromatic ring optionally replace will just like in right
Seek the one or more substituent groups limited in 1.
3. technique according to claim 1, compounds of formula I Ia and Formula II compound are IIa.
4. technique according to claim 2, compounds of formula I Ia, Formula II compound are IIa and formula III chemical combination
Object is IIIa.
5. such as the Formula II compound limited in claim 1.
6. Formula II a compounds.
7. the technique of Formula VII compound is used to prepare, including Formula II compound is converted into Formula VII in the presence of a reducing agent
Compound, wherein nitrile part keep complete.
8. technique according to claim 7, compound of formula VTI is Formula VII a compounds and Formula II compound is
Formula II a compounds.
9. the technique of Formulas I a compound or its salts is used to prepare, including in the presence of a reducing agent converting Formula II a compounds
For Formulas I a compounds, it is characterised in that Formula II a compounds are first converted into Formula VII a compounds, and then Formula VII a compounds turn
Formulas I a compounds are turned to, wherein Formula VII a compounds are optionally separated.
10. the technique of organic compound is used to prepare, including being converted into Formula II compound as limited in claim 1
Compound of formula I and the step of compound of formula I is converted into organic compound.
11. be used to prepare the technique of Idalopirdine, including Formula II a compounds are converted into Formulas I a compounds and by Formulas I a
Compound is converted into the step of Idalopirdine.
12. such as the application of the Formula II compound that is limited in claim 1 as intermediate in the synthesis of organic compound.
13. application of the Formula II a compounds as intermediate in the synthesis of Idalopirdine.
14. such as the application of the Formula II compound that is limited in claim 1 in formula I or VII compound.
15. application according to claim 14, compound of formula H is Formula II a compounds and Formulas I and VII chemical combination
Object is respectively Formulas I a or VIIa compound.
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| PCT/EP2016/025121 WO2017067670A1 (en) | 2015-10-23 | 2016-10-19 | A novel process for the preparation of tryptamines and derivatives thereof |
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